Diagnosis and treatment of pituitary tumours: a starting-point for manipulation of cancer with hypothalamic hormones

In order to make a well-founded choice between the therapeutic modalities presently available it is important to have a clear picture of the differences in the natural history of the various types of pituitary tumours. One of the most important questions regards possible differences in the tendency of the various tumours to grow extrasellarly. A related question concerns the relationship between the secretion rate of growth hormone, prolactin etc. and the size of the respective tumour. In other words: do high serum levels of these hormones in general indicate the presence of a large tumour and do moderately increased levels point to a smaller tumour? A parallel and for the management sometimes crucial question is a possible relationship between tumour growth rate and the age of the patient. Furthermore, one can ask what - in a therapeutic sense - may be the significance of a combined secretion of growth hormone and prolactin by a pituitary tumour. The therapeutic part of our study concerns the efficacy and the rapidity, with which the desired therapeutic endpoint may be reached by means of (transsphenoidal) surgery, irradiation or the combination of these treatments in the various types of pituitary tumours. Furthermore, we have considered the value of medical treatment as an additional or - possibly - as primary therapy

The clinical significance of epidermal growth factor receptor (egf-r) in human breast cancer: A review on 5232 patients

Epidermal growth factor (EGF) is a 53-aminoacid polypeptide (mol wt 6.045 K) that can influence proliferation and differentiation of a wide variety of cells (1–6). EGF as well as transforming growth factor-α (TGF-α), both of which can activate EGF receptor (EGF-R), are probably produced locally in many tissues as local growth factors rather than as systemic hormones. There is evidence that EGF plays a role in carcinogenesis and that the EGF-stimulated growth regulatory system (apart from that of benign cells) is also involved in proliferation of malignant cells (3). Cellular events are induced by EGF via its cell membrane receptor (EGF-R). The EGF-R is a 170 K glycoprotein that can be divided into an extracellular domain binding EGF or TGF-α, a short transmembrane domain, and an intracellular domain carrying tyrosine kinase activity (7). This intracellular domain shows close sequence homology with the c-erbB-2 and with neu (8), the rat homolog of c-erbB-2 oncogene. Increased expression of the EGF-R gene has been found in a variety of tumors, generally indicating a more aggressive behavior of cancers compared to those with low or normal expression (9–10) although this association is not invariant (11). EGF-R has been identified by several methods including radioligand binding assays, autoradiography, immunocytohistochemistry, immunoenzymatic assays, and measurement of EGF-R transcripts

Thymidine kinase and thymidylate synthase in advanced breast cancer: response to tamoxifen and chemotherapy

Thymidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in the de novo pathway of pyrimidine synthesis, which is necessary for DNA synthesis. Thymidine kinase (TK) plays a key role in the complementary or alternative salvage pathway of pyrimidine synthesis in acute or pathological tissue stress. In the present study, the activity levels of TS and TK were determined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60%) responding patients, the median response duration was 23 months for tumors with low TK activity, 15 months for tumors with intermediate TK activity, and 13 months for tumors with high TK activity (P = 0.003). In Cox multivariate analysis corrected for classical predictive factors including estrogen receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatment. Tumor TS activity levels were not significantly associated with the efficacy of tamoxifen treatment. In 121 patients who became resistant to tamoxifen or additional endocrine treatments and who received 5-FU-containing polychemotherapy, tumor TK activity was not significantly related to the efficacy of chemotherapy. Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). In Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemotherapy. In conclusion, for patients with recurrent breast cancer, high tumor TK activity is a significant marker of poor clinical outcome on tamoxifen therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU-containing polychemotherapy when applied after tumor progression on endocrine therapy

The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer

A variety of serine proteases, including urokinase-type plasminogen activator (uPA), plasmin,and polymorphonuclear leukocyte elastase (PMN-E), have been implicated in the processes of tumor cell invasion and metastasis. Besides degrading of matrix proteins, PMN-E has been shown to be able to cleave and inactivate plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of uPA, and alpha2-antiplasmin, the natural inhibitor of plasmin, thus enabling an uncontrolled matrix degradation by the fibrinolytic enzymes. Because only limited data are available on a relationship between the tumor level of PMN-E and prognosis in primary breast cancer patients, in the present study we have measured with an ELISA the levels of PMN-E (in complex with alpha1-proteinase inhibitor) in cytosolic extracts of 1143 primary breast tumors. Levels of complexed PMN-E have been correlated with the lengths of metastasis-free survival (MFS), relapse-free survival, and overall survival, and a comparison was made with data previously obtained for uPA and PAI-1. Our results show that patients with a high PMN-E level in their primary tumor had a rapid relapse and an early death compared with patients with a low tumor level of PMN-E. This held true for node-negative and node-positive subgroups of patients as well. The relationship of PMN-E with a poor prognosis was especially obvious during short-term follow-up (0-60 months). In Cox multivariate regression analysis, corrected for the traditional prognostic factors, PMN-E was an independent prognostic factor, and high levels of PMN-E were associated with a poor MFS [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.23-2.16; P < 0.001], relapse-free survival (HR, 1.45; 95% CI, 1.10-1.89; P = 0.01), and overall survival (HR, 1.64; 95% CI, 1.20-2.23; P = 0.003). Furthermore, in all three multivariate models, PMN-E still added significantly to the model after the additional inclusion of the uPA. PMN-E was an independent prognostic factor for MFS even in the multivariate analysis including the traditional clinical prognostic factors and the strong established biochemical prognostic factors uPA and PAI-1. Our present study suggests that PMN-E is associated with breast cancer metastasis, and knowledge of the tumor PMN-E status might be helpful in selecting the appropriate individualized (adjuvant) treatment for patients with breast cancer

Pleiotropic actions of suramin on the proliferation of human breast-cancer cells in vitro

Suramin, a non‐specific growth factor antagonist, is currently under investigation for treatment of cancer patients. We studied its action on 6 different human breast‐cancer cell lines in vitro. In complete growth medium, pleiotropic effects were observed with respect to cell proliferation, i.e. suramin is stimulatory at low concentrations and inhibitory at higher concentrations, for 4 of the 6 cell lines studied. The various cell lines showed marked differences with respect to the antiproliferative action of suramin, the Evsa‐T cells being by far the most sensitive ones. A suramin concentration of 100 μg/ml brought about a 100% stimulation of the proliferation of ZR/HERc cells, ZR 75.1 cells ectopically expressing a human epidermal growth factor receptor (EGF‐R) cDNA. Although less pronounced (10 to 60% stimulation), a similar response was observed for the parent ZR 75.1 cells, as well as for T‐47D and MDA‐MB‐231 cells. The non‐specificity of the action of suramin was established by the observation that suramin‐induced inhibition of cell proliferation could be abolished by insulin‐like growth factor‐1 (IGF‐I) or basic fibroblast growth factor (bFGF), and even by estradiol, both in complete growth medium and under defined serum‐free conditions. Our data indicate that suramin exerts pleiotropic effects on the proliferation of human breast cancer cells in vitro, and confirm the non‐specific nature of its action. The stimulatory effect of low concentrations of suramin on the proliferation of breast cancer cells may have important consequences for breast cancer patients treated with suramin. Copyrigh

Treatment of breast cancer with different antiprogestins: Preclinical and clinical studies

Abstract Treatment with antiprogestins in a new treatment modality for breast cancer. Previously, in rats with DMBA-induced mammary tumors we observed significant growth inhibitory effects of chronic treatment with the antiprogestin mifepristone (RU486). In addition, in 11 postmenopausal breast cancer patients, we observed one objective response, six instances of short-term stable disease, and four instances of progressive disease. Side-effects appeared mainly due to antiglucocorticoid properties of the drug. Increased plasma estradiol levels were observed which probably resulted from ovarian (rat) and adrenal (patients) steroidogenesis. Combined treatment with an antiestrogen in the rat model caused additive growth inhibitory effects. Tumor inhibition after single treatment with mifepristone or tamoxifen was 90 and 75%, respectively. In contrast, when combined, tumor remission similar to that caused by LHRH-agonist treatment (50%) was observed. Even higher tumor remission was found after combined treatment with mifepristone plus LHRH-agonist (75%). In first studies in the rat model we observed significant tumor growth inhibitory effects with two new antiprogestins of seemingly greater potency which cause less unfavorable endocrine side-effects. In conclusion: combined treatment (antiprogestin plus antiestrogen or LHRH-agonist) may be of value in endocrine therapy of breast cancer

The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters

To analyse the clinical significance of the presence of androgen receptors (AR) in breast carcinomas, clinical and histological parameters of 153 primary breast carcinomas (median follow-up 46 months) were examined. Oestrogen (ER) and progesterone receptor (PR) levels were determined in cytosol preparations using enzyme immunoassay assays and in cryostat sections by immunohistochemistry. AR and Ki-67 levels were only determined immunohistochemically. Data were analysed by uni- and multivariate models. 94/153 (61%) breast carcinomas were ER+ PR+ AR+, while 14 cases were only positive for AR. All grade III tumours (n = 17) were steroid receptor negative and 14 (76%) of these cases demonstrated high Ki-67 values suggestive of more aggressive behaviour. Strikingly, 14 ductal carcinomas negative for ER and PR were positive for AR. In univariate analysis, AR as well as ER, tumour size, lymph node status, grade and Ki-67 proved to be significant prognostic factors for disease free survival (DFS). Multivariate analysis, however, showed lymph node status, tumour size and ER status to be the only independent prognostic factors for DFS within this model. We conclude that simple histological and cell biological parameters, including AR, can be used to select high- and low-risk patients at the time of primary surgery and can provide valuable information on treatment options